Currently for lymphoma patients, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/ computed tomography (CT) is used for interim restaging or therapy monitoring after 1-4 cycles of chemo-/chemoimmunotherapy. An excellent negative predictive value (NPV) of >80% with only a moderate positive predictive value (PPV) of between 25%- 70% has been reported. It has been shown that a substantial portion of the false-positive FDG-PET findings in this setting were caused by early post-therapy inflammatory changes. This hampers the accuracy and reliability of this test and, hence, its acceptance as an early prognostic tool in the clinical practice setting. An important recent advance in the area of molecular imaging of lymphoma is the development of the PET tracer18F-fluorothymidine (FLT) as an in vivo marker of cell proliferation. FLT uptake in lymphomas has been shown to be proportional to the Ki-67 index, a recognized histopathological marker of cell proliferation and since less affected by postherapy inflammatory changes caused by macrophages/monocyte infiltration, it is also a more tumor-specific tracer when compared to FDG. This higher tumor- specificity may be advantageous in early response assessment following chemo-/chemoimmunotherapy, radiation therapy (RT) or combined modality therapy. In this application, we propose to compare the predictive values of interim FLT- PET/CT and FGD-PET/CT in diffuse large B-cell lymphoma (DLBCL) patients after 2 cycles of R-CHOP chemotherapy. Our hypothesis is that FLT-PET/CT will have a substantially higher PPV when compared to FDG-PET/CT (i.e., e 91% vs. d 68%) while providing a similar or only slightly lower NPV and, therefore, prove superior to FDG-PET in this setting. We propose to prospectively study 137 DLBCL patients at 5 institutions. Study patients will be scanned by FLT-PET/CT and FDG-PET/CT 18-24 days after the second cycle of R-CHOP. After completion of six cycles of chemotherapy, conventional staging methods (CSM) will be performed in all patients to assess response and determine appropriate patient management. Patients will be followed for event-free survival (EFS) and overall survival (OS) for at least 24 months post- therapy or until definite determination of persistent disease (by biopsy) or disease progression (both considered an event). Specifically, we intend to: 1. Investigate whether the PPV of FLT-PET/CT is significantly higher (i.e., e 91% vs. d 68%) than that of FDG-PET/CT by following-up patients for at least 24 months posttherapy or until evidence of or disease progression. 2. Investigate whether the EFS of patients with FDG-PET/CT-positive and FLT-PET/CT negative scans is not significantly lower than that of patients with concordantly negative FDG-PET/CT and FLT-PET/CT scans (i.e., <65% vs. 85%) and, therefore confirming that the NPV of FLT-PET/CT is similar to that of FDG-PET/CT. 3. Correlate interim FLT- PET/CT and FDG-PET/CT with the International Prognostic Index (IPI), a well-established predictor of outcome in DLBCL. The demonstration of superiority of FLT-PET/CT over FDG-PET/CT is expected to lead to greater confidence in using interim PET in patient management. This increased reliability could potentially even render repeat biopsy unnecessary for midtherapy treatment decisions. This would represent a significant advance in the use of PET imaging for personalized therapy with an expectedly positive impact on patient management and/or outcome of patients with DLBCL. PUBLIC HEALTH RELEVANCE: Currently for lymphoma patients, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/ computed tomography (CT) is used for interim restaging or therapy monitoring after 1-4 cycles of chemo- /chemoimmunotherapy. However, its accuracy is suboptimal which hampers its acceptance as an early prognostic tool in the clinical practice setting. In this investigation, we will determine whether the novel tracer 18F-fluorothymidine (FLT) combined with CT (FLT-PET/CT) is superior in this setting. The demonstration of superiority of FLT-PET/CT over FDG-PET/CT is expected to lead to greater confidence in using interim PET in patient management potentially rendering repeat biopsy unnecessary for midtherapy treatment decisions. This would represent a significant advance in the use of PET imaging for personalized therapy with an expectedly positive impact on patient management and/or outcome of patients with lymphoma.